LETTER
Synthesis of Novel Glycopeptidomimetics
1465
Bz-Leu-Ala-N-OSer( -Glc(OAc)4)-Asp-Phe-NH2 (1 ): 1H NMR
(500 MHz, DMSO-d6) 11.37 (s, 1 H), 8.40 (d, 1 H, J = 6.6 Hz),
8.38 (d, 1 H, J = 7.2 Hz), 8.14 (d, 1 H, J = 6.8 Hz), 7.86 (d, 3 H, J =
7.3 Hz), 7.56–7.41 (m, 3 H), 7.34–7.04 (m, 7 H), 5.25 (t, 1 H, J =
9.5 Hz), 4.91 (t, 1 H, J = 9.7 Hz), 4.84 (d, 1 H, J = 7.9 Hz), 4.77 (dd,
1 H, J = 8.4, 9.1 Hz), 4.58–4.48 (m, 2 H), 4.42–4.34 (m, 1 H), 4.32
(br s, 1 H), 4.22–4.12 (m, 2 H), 4.05–3.88 (m, 3 H), 3.75 (d, 1 H,
J = 9.9 Hz), 3.02 (dd, 1 H, J = 4.9, 14.0 Hz), 2.85 (dd, 1 H, J = 8.5,
14.0 Hz), 2.67 (dd, 1 H, J = 6.7, 16.7 Hz), 2.00 (s, 3 H), 1.98 (s, 6
H), 1.93 (s, 3 H), 1.72–1.60 (m, 2 H), 1.54–1.44 (m, 1 H), 1.18 (d,
3 H, J = 6.7 Hz), 0.89 (d, 3 H, J = 6.0 Hz), 0.86 (d, 3 H, J = 5.9 Hz).
Bz-Leu-Ala-N-OSer( -Glc)-Asp-Phe-NH2 (1): 1H NMR (500
MHz, DMSO-d6) 11.37 (s, 1 H, N-OSer-NH), 8.57 (d, 1 H, J = 8.5
Hz, Asp-NH), 8.39 (d, 1 H, J = 7.9 Hz, Leu-NH), 8.16 (d, 1 H, J =
6.4 Hz, Ala-NH), 7.91–7.84 (m, 3 H, Bz-H, Phe-NH), 7.55–7.42
(m, 3 H), 7.33–7.10 (m, 7 H), 4.58–4.50 (m, 2 H, Leu-C H, Asp-
C H), 4.42-4.33 (m, 2 H, N-OSer-C H, Phe-C H), 4.24 (d, 1 H, J =
7.8 Hz, anomeric H), 4.21–4.15 (m, 1 H, Ala-C H), 3.92–3.85 (m,
1 H, N-OSer-C H), 3.80–3.76 (m, 1 H, N-OSer-C H), 3.72–3.65 (m, 1
H), 2.90–2.81 (m, 1 H, Phe-C H), 1.73–1.60 (m, 2 H, Leu-C H),
1.53–1.44 (m, 1 H, Leu-C H), 1.20 (d, 3 H, J = 6.7 Hz, Ala-C H),
0.89 (d, 3 H, J = 6.0 Hz, Leu-C H), 0.86 (d, 3 H, J = 6.0 Hz, Leu-
C H); MALDI-TOF-MS Calcd for C38H52N6O15 [M + Na]+ 855.35,
found 855.32
dephthaloylated 11 with HATU-HOAt-NEM followed by
debenzylation in 40~50% overall yield, which was slight-
ly lower than their corresponding O-glycosylated trimers
10 (Scheme 4). The N-glycopeptidomimetics 3 and 4
were produced by fragment coupling of trimers 12 to C-
terminal dipeptide on solid support and subsequent
deacetylation with 6~10 mM NaOMe in 20~30% yield.10
O
O
1. NH2NH2, CH2Cl2
N
O
OBn
O
2. Bz-Leu-Ala-OH, DMF
HATU, HOAt, NEM
3. Pd/C, H2, MeOH
O
NHR
11
12a: 50%
12b: 43%
O
O
H
N
O
BzHN
N
OH
O
R = β-Glc(OAc)4 (a)
β-Lac(OAc)7 (b)
H
O
12
NHR
Bz-Leu-Ala-N-OSer( -Mal(OAc)7)-Asp-Phe-NH2 (2 ): 1H NMR
(500 MHz, DMSO-d6) 11.37 (s, 1 H), 8.40 (d, 1 H, J = 7.8 Hz),
8.39 (d, 1 H, J = 8.0 Hz), 8.14 (d, 1 H, J = 6.3 Hz), 7.87 (d, 3 H, J =
7.3 Hz), 7.55–7.42 (m, 3 H), 7.34–7.05 (m, 7 H), 5.30–5.24 (m, 2
H), 5.21 (t, 1 H, J = 10.0 Hz), 4.98 (t, 1 H, J = 9.7 Hz), 4.86 (dd, 1
H, J = 3.3, 10.5 Hz), 4.82 (d, 1 H, J = 8.0 Hz), 4.67 (dd, 1 H, J = 8.3,
8.9 Hz), 4.58–4.48 (m, 2 H), 4.42–4.28 (m, 3 H), 4.22–4.11 (m, 3
H), 4.03–3.86 (m, 5 H), 3.73 (d, 1 H, J = 10.2 Hz), 3.01 (dd, 1 H, J
= 4.9, 14.0 Hz), 2.85 (dd, 1 H, J = 8.5, 14.0 Hz), 2.66 (dd, 1 H, J =
6.7, 16.5 Hz), 2.05 (s, 3 H), 2.01 (s, 3 H), 1.98 (s, 6 H), 1.94 (s, 6
H), 1.93 (s, 3 H), 1.72–1.61 (m, 2 H), 1.56–1.44 (m, 1 H), 1.18 (d,
3 H, J = 6.7 Hz), 0.88 (d, 3 H, J = 6.1 Hz), 0.86 (d, 3 H, J = 5.9 Hz).
Bz-Leu-Ala-N-OSer( -Mal)-Asp-Phe-NH2 (2): 1H NMR (500
MHz, DMSO-d6) 11.37 (s, 1 H, N-OSer-NH), 8.56 (br s, 1 H, Asp-
NH), 8.39 (d, 1 H, J = 8.1 Hz, Leu-NH), 8.16 (br s, 1 H, Ala-NH),
7.91–7.83 (d, J = 7.1 Hz, 3 H, Bz-H, Phe-NH), 7.56–7.41 (m, 3 H),
7.33–7.07 (m, 7 H), 5.00 (br s, 1 H, anomeric H), 4.54 (br s, 2 H,
Leu-C H, Asp-C H), 4.37 (br s, 2 H, N-OSer-C H, Phe-C H), 4.30 (d,
O
H
N
N
H
SPPS
FmocHN
FmocHN
O
PS Rink amide linker
1. 20% piperidine
OtBu
3': Bz-Leu-Ala-N-OAsn(β-Glc(OAc)4)-Leu-Ser-NH2
4': Bz-Leu-Ala-N-OAsn(β-Lac(OAc)7)-Leu-Ser-NH2
2. 12, HATU, HOAt
NEM
3. TFA:TES (98:2)
6 - 10 mM NaOMe
3' and 4'
3 and 4
MeOH
overall yield 1: 25%, 2: 30%
Scheme 4
In summary, glycosylated peptidomimetics bearing N- 1 H, J = 6.8 Hz, anomeric H), 4.18 (br s, 1 H, Ala-C H), 3.94–3.84
(m, 1 H, N-OSer-C H), 3.82–3.75 (m, 1 H, N-OSer-C H), 2.91–2.80
(m, 1 H, Phe-C H), 2.72–2.61 (m, 1 H, Asp-C H), 1.73–1.59 (m, 2
H, Leu-C H), 1.55–1.42 (m, 1 H, Leu-C H), 1.20 (d, 3 H, J = 5.9
Hz, Ala-C H), 0.89 (d, 3 H, J = 4.9 Hz, Leu-C H), 0.86 (d, 3 H, J =
and O-glycosylated -aminooxy acids were efficiently
prepared by both solid- and solution-phase synthetic tech-
niques. We are currently investigating the effects of car-
bohydrates on the secondary structure of peptidomimetics
and the molecular basis of carbohydrate-protein interac-
tions on these glycopeptidomimetics.
5.4 Hz, Leu-C H); MALDI-TOF-MS Calcd for C44H62N6O20 [M +
Na]+ 1017.40, found 1017.85.
Bz-Leu-Ala-N-OAsn( -Glc(OAc)4)-Leu-Ser-NH2 (3 ): 1H NMR
(500 MHz, DMSO-d6) 11.38 (s, 1 H), 8.89 (d, 1 H, J = 9.1 Hz),
8.62 (d, 1 H, J = 6.1 Hz), 8.41 (d, 1 H, J = 7.9 Hz), 8.11 (br s, 1 H),
7.86 (d, 2 H, J = 7.4 Hz), 7.66 (d, 1 H, J = 6.9 Hz), 7.57–7.38 (m, 3
H), 7.11 (s, 2 H), 5.38 (t, 1 H, J = 9.3 Hz), 5.32 (t, 1 H, J = 9.5 Hz),
4.92–4.83 (m, 2 H), 4.80 (t, 1 H, J = 9.4 Hz), 4.63–4.55 (m, 1 H),
4.55–4.46 (m, 1 H), 4.26–4.00 (m, 4 H), 3.97 (d, 1 H, J = 11.6),
3.65–3.52 (m, 2 H), 1.99 (s, 3 H), 1.98 (s, 3 H), 1.92 (s, 3 H), 1.87
(s, 3 H), 1.72–1.58 (m, 3 H), 1.56–1.39 (m, 3 H), 1.18 (d, 3 H, J =
6.8 Hz), 0.93–0.72 (m, 12 H).
Bz-Leu-Ala-N-OAsn( -Glc)-Leu-Ser-NH2 (3): 1H NMR (500
MHz, DMSO-d6) 11.40 (s, 1 H, N-OAsn-NH), 8.71 (d, 1 H, J = 7.9
Hz, N-OAsn side chain NH), 8.62 [br s, 1 H, Leu(4)-NH], 8.42 [d, 1
H, J = 7.4 Hz, Leu(1)-NH], 8.15 (br s, 1 H, Ala-NH), 7.86 (m, 2 H),
7.77 (d, 1 H, J = 7.0 Hz, Ser-NH), 7.57–7.41 (m, 3 H), 7.09 (s, 1 H,
NH2), 7.02 (s, 1 H, NH), 4.71 (t, 1 H, J = 8.6 Hz, anomeric H), 4.62–
Typical Experimental Procedure: Synthesis of Glycosylated
Peptidomimetics by Fragment Coupling.
Glycosylated trimer (3 equiv) was coupled to dipeptide assembled
by conventional solid phase peptide synthesis on PS-PEG Rink
amide resin on a 10–15 mol scale, using HATU (3 equiv), HOAt
(3 equiv) and NEM (4 equiv) in DMF for 6 h. After coupling reac-
tion, the resin was treated with TFA–TES (98:2) for 1.5 h. The
crude product was purified by preparative RP-HPLC with a gradient
of 5–100% CH3CN in water (0.1% TFA) over 85 min. Deacetyla-
tion was performed by treating the isolated peptidomimetics with 6–
10 mM NaOMe in MeOH for 1 h at room temperature. The crude
product was purified by RP-HPLC under the same conditions.
Synlett 2002, No. 9, 1463–1466 ISSN 0936-5214 © Thieme Stuttgart · New York